dbSNP rs4986782: NAT1:p.Arg187Gln (chr8-18222607-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000662.8(NAT1):c.560G>A(p.Arg187Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 1,612,688 control chromosomes in the GnomAD database, including 290 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.014 ( 29 hom., cov: 32)

Exomes 𝑓: 0.017 ( 261 hom. )

Consequence

NAT1
NM_000662.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.64

Publications

71 publications found

Variant links:

COSMIC-nc: COSV104604952

Genes affected

NAT1 (HGNC:7645): (N-acetyltransferase 1) This gene is one of two arylamine N-acetyltransferase (NAT) genes in the human genome, and is orthologous to the mouse and rat Nat2 genes. The enzyme encoded by this gene catalyzes the transfer of an acetyl group from acetyl-CoA to various arylamine and hydrazine substrates. This enzyme helps metabolize drugs and other xenobiotics, and functions in folate catabolism. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

NAT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033810735).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.014 (2124/152242) while in subpopulation NFE AF = 0.0187 (1269/68012). AF 95% confidence interval is 0.0178. There are 29 homozygotes in GnomAd4. There are 1115 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2124 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAT1	NM_000662.8 link	c.560G>A	p.Arg187Gln	missense_variant	Exon 3 of 3	ENST00000307719.9	NP_000653.3	P18440

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAT1	ENST00000307719.9 link	c.560G>A	p.Arg187Gln	missense_variant	Exon 3 of 3	1	NM_000662.8	ENSP00000307218.4		P18440

Frequencies

GnomAD3 genomes

AF:

0.0140

AC:

2125

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00319

Gnomad AMI

AF:

0.0187

Gnomad AMR

AF:

0.00884

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.0496

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0187

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0145

AC:

3616

AN:

249910

AF XY:

0.0142

show subpopulations

Gnomad AFR exome

AF:

0.00321

Gnomad AMR exome

AF:

0.00589

Gnomad ASJ exome

AF:

0.00312

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0441

Gnomad NFE exome

AF:

0.0194

Gnomad OTH exome

AF:

0.0130

GnomAD4 exome

AF:

0.0175

AC:

25527

AN:

1460446

Hom.:

261

Cov.:

AF XY:

0.0170

AC XY:

12324

AN XY:

726512

show subpopulations

African (AFR)

AF:

0.00246

AC:

AN:

33358

American (AMR)

AF:

0.00697

AC:

310

AN:

44448

Ashkenazi Jewish (ASJ)

AF:

0.00300

AC:

AN:

26032

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39688

South Asian (SAS)

AF:

0.00343

AC:

295

AN:

86058

European-Finnish (FIN)

AF:

0.0438

AC:

2337

AN:

53376

Middle Eastern (MID)

AF:

0.00400

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0194

AC:

21593

AN:

1111438

Other (OTH)

AF:

0.0134

AC:

808

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1444

2888

4332

5776

7220

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

802

1604

2406

3208

4010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0140

AC:

2124

AN:

152242

Hom.:

Cov.:

AF XY:

0.0150

AC XY:

1115

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00318

AC:

132

AN:

41562

American (AMR)

AF:

0.00883

AC:

135

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00249

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0496

AC:

525

AN:

10588

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0187

AC:

1269

AN:

68012

Other (OTH)

AF:

0.0114

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

114

228

341

455

569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0168

Hom.:

117

Bravo

AF:

0.0107

TwinsUK

AF:

0.0205

AC:

ALSPAC

AF:

0.0166

AC:

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0169

AC:

145

ExAC

AF:

0.0141

AC:

1714

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0163

EpiControl

AF:

0.0188

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.054

T;T;T;T;.;T

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.74

.;T;.;.;T;.

MetaRNN

Benign

0.0034

T;T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.1

L;L;L;L;.;L

PhyloP100

1.6

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.5

N;N;N;N;N;N

REVEL

Benign

0.068

Sift

Benign

0.36

T;T;T;T;T;T

Sift4G

Benign

0.46

T;T;T;T;T;T

Polyphen

0.81

P;P;P;P;P;P

Vest4

0.043

MPC

0.039

ClinPred

0.033

GERP RS

1.2

Varity_R

0.095

gMVP

0.56

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over